Newly synthesized endoplasmic reticulum (ER) proteins are subjected to inspection by the ER quality control machinery to ensure that only properly folded molecules can traffic to their final destination. ER proteins that cannot reach their native state due to genetic defects are exported out of the ER and into the cytosol by a multi- step process referred to as dislocation, followed by proteasome degradation generally referred to as ER-associated degradation (ERAD). Human diseases whose genetic defects prevent the protein from reaching its native conformation include pulmonary diseases (e.g. emphysema and cystic fibrosis), blood disorders (e.g. protein C deficiency), and neurological disorders (e.g. neuronal ceroid lipofuscinoses and Fabri disease). In addition, toxins such as cholera and ricin toxin have exploited the transport of proteins from the ER to cytosol to gain access to the cytosol and alter cellular metabolism. Strikingly, viruses have evolved to utilize the ERAD pathway to evade immune detection and persist within the host. Human cytomegalovirus (HCMV) unique short (US)2 and US11 gene products have co-opted ERAD to mediate the destruction of the immunological protein major histocompatibility complex (MHC) class I heavy chain to limit viral clearance by cytotoxic T cells. In fact, how proteins are extracted from the ER in mammalian cells was initially characterized using HCMV US2- and US11-expressing cells and this cell system continues to identify key ERAD components. An important feature of US2 and US11-mediated class I destruction is the fast kinetics (t1/2 ~5 min) of class I degradation. The short half-life of class I heavy chains in US2 and US11 cells was adapted into a high-throughput screen using a class I heavy chain chimera consisting of enhanced green fluorescence protein and class I heavy chain. Two compounds referred to as eeyarestatin I and II were identified to stabilize class I heavy chains as well as other misfolded proteins, T cell receptor 1 chain and an 11-antitrypsin variant. The screening of larger and more diverse chemical libraries would allow for the discovery of additional compounds that stabilize ER degradation substrates. These inhibitors would be effective agents against genetic disorders caused by misfolded ER proteins and pathogens that utilize the ERAD pathway. PUBLIC HEALTH RELEVANCE: Human diseases caused by genetic defects of endoplasmic reticulum (ER) proteins are degraded by process referred to as ER-associated degradation (ERAD). Some pathogens such as human cytomegalovirus have evolved to utilize ERAD to escape immune clearance. The identification of drugs that can rescue genetically defective proteins from degradation and/or interfere with viral immune evasion would prevent the onset of ERAD related diseases and allow the immune system to eliminate the virus.